Goal: Generate a mouse model of FLC
Principal Investigator: Sean Ronnekleiv-Kelly, MD, Surgical Oncology
The purpose of this study was to generate a robust pre-clinical murine model of FLC that can provide a basis for understanding factors contributing to FLC formation, and for therapeutic development. The study proposed to develop a mouse model of FLC using a gene editing approach in a susceptible population, using hydrodynamic delivery of gene editing material to the liver via retro-orbital injection at age 7-8 weeks in mice with varying susceptibility to liver tumor formation. This included C57BL/6 mice, FVB mice, C3H mice, Balb/c mice and DBA/2 mice, which have a range of 2-3 fold lower vulnerability to 3-7 fold higher susceptibility to liver cancer development. In this manner, they wanted to identify if different susceptibilities to liver tumor formation causes earlier onset / more aggressive cancer, which could then ultimately improve the understanding of FLC development. In a second subset of the same mouse strains, they performed retro-orbital injection of the mice at age 2 weeks, a timeframe selected because the fusion gene mutation is an early somatic event in humans (i.e. peak age of FLC diagnosis is 21 years). Most existing studies targeted the DNAJB1-PRKACA mutation to the liver at age 7-8 weeks. Targeting the gene editing material to generate the fusion gene at 2 weeks (when liver cells are still actively dividing) may create a different tumor phenotype compared to existing models.